Hydrogen bonds and their relative strengths in proteins are of importance for understanding protein structure and protein motions. The correct strength of such hydrogen bonds is experimentally known to vary greatly from Ϸ5-6 kcal͞mol for the isolated bond to Ϸ0.5-1.5 kcal͞mol for proteins in solution. To estimate these bond strengths, here we suggest a direct novel kinetic procedure. This analyzes the timing of the trajectories of a properly averaged dynamic ensemble. Here we study the observed rupture of these hydrogen bonds in a molecular dynamics calculation as an alternative to using thermodynamics. This calculation is performed for the isolated system and contrasted with results for water. We find that the activation energy for the rupture of the hydrogen bond in a ␤-sheet under isolated conditions is 4.76 kcal͞mol, and the activation energy is 1.58 kcal͞mol for the same ␤-sheet in water. These results are in excellent agreement with observations and suggest that such a direct calculation can be useful for the prediction of hydrogen bond strengths in various environments of interest.T he strength of the hydrogen bond in the linking of protein structures particular in a water environment is of essential importance to predict the activity of proteins such as enzyme action, protein folding, binding of proteins, and many other processes (1, 2). Although much has been written on protein dynamics in water (3), a detailed energy calculation including the correct water environment has been difficult to put into a computational framework. The energetics of hydrogen bonds within proteins is known to undergo large changes in water. The effect of water is also process dependent, so it is different here from protein signal transport (4). Such environmental changes in a hydrogen bond strength are important to the understanding of protein interactions, including drug design (5, 6). The drugreceptor hydrogen bond is operative in many applications (7).Hydrogen bonds are one of the major structural determinants, controlling active configurations by connecting protein structure in a fluxional equilibrium. The making and breaking of hydrogen bonds profoundly affects the rates and dynamic equilibria, which are responsible for much of the biological activity of proteins. This behavior is strongly medium dependent, so the action of these hydrogen bonds in isolated systems is quite different from the action in a water environment. The complex environment presented to the hydrogen bond by water is not easy to incorporate in calculations, but it is of major relevance, and results obtained need to be checked against experiments. A huge and complex phase space contributes to the effects of entropy on the hydrogen bond, particularly in water, and thus influences the free energy of these bonds. The general task of assessing the entropic contributions to the dynamic strength of these bonds is a matter of extensive research (8) and is difficult to quantify. Furthermore, it must be recognized that various relevant bonding environments will...

Biological systems often transport charges and reactive processes over substantial distances. Traditional models of chemical kinetics generally do not describe such extreme distal processes. In this Review, an atomistic model for a distal transport of information, which was specifically developed for peptides, is considered. Chemical reactivity is taken as the result of distal effects based on two-step bifunctional kinetics involving unique, very rapid motional properties of peptides in the subpicosecond regime. The bifunctional model suggests highly efficient transport of charge and reactivity in an isolated peptide over a substantial distance; conversely, a very low efficiency in a water environment was found. The model suggests ultrafast transport of charge and reactivity over substantial molecular distances in a peptide environment. Many such domains can be active in a protein.

As a simple model of the Brownian motor, we consider hopping motion of a particle in a periodic asymmetric double-well potential which randomly switches between two states. The potential profiles of the states are identical but shifted by half a period. The current and the efficiency are explicitly calculated as functions of the parameters of the model, including also a load force. Such a flashing ratchet is shown to be particularly efficient, with the efficiency tending to unity when the highest peak of the potential is high enough to suppress the backward motion.

We suggest that the H-bond in proteins not only mirrors the motion of hydrogen in its own atomistic setting but also finds its origin in the collective environment of the hydrogen bond in a global lattice of surrounding H2O molecules. This water lattice is being perturbed in its optimal entropic configuration by the motion of the H-bond. Furthermore, bonding interaction with the lattice drop the H-bond energy from some 5 kcal/mol for the pure protein in the absence of H2O, to some 1.6 kcal/mol in the presence of the H2O medium. This low value here is determined in a computer experiment involving MD calculations and is a value close to the generally accepted value for biological systems. In accordance with these computer experiments under ambient conditions, the H-bond energy is seriously depressed, hence confirming the subtle effect of the H2O medium directly interacting with the H-bond and permitting a strong fluxional behavior. Furthermore, water produces a very large change in the entropy of activation due to the hydrogen bond breakage, which affects the rate by as much as 2 orders of magnitude. We also observe that there is an entire ensemble of H-bond structures, rather than a single transition state, all of which contribute to this H-bond. Here the model is tested by changing to D2O as the surrounding medium resulting in a substantial solvent isotope effect. This demonstrates the important influence of the environment on the individual hydrogen bond.

Our previous finding and the given mechanism of charge and electron transfer in polypeptides are here integrated in a bifunctional model involving electronic charge transfer coupled to special internal rotations. Present molecular dynamics simulations that describe these motions in the chain result in the mean first passage times for the hopping process of an individual step. This ''rest and fire'' mechanism is formulated in detail-i.e., individual amino acids are weakly coupled and must first undergo alignment to reach the special strong coupling. This bifunctional model contains the essential features demanded by our prior experiments. The molecular dynamics results yield a mean first passage time distribution peaked at about 140 fs, in close agreement with our direct femtosecond measurements. In logic gate language this is a strongly conducting ON state resulting from small firing energies, the system otherwise being a quiescent OFF state. The observed time scale of about 200 fs provides confirmation of our simulations of transport, a model of extreme transduction efficiency. It explains the high efficiency of charge transport observed in polypeptides. We contend that the moderate speed of weak coupling is required in our model by the bifunctionality of peptides. This bifunctional mechanism agrees with our data and contains valuable features for a general model of long-range conductivity, final reactivity, and binding at a long distance. Charge conductivity in biomolecules has become a general topic of substantial current interest (1, 2). This phenomenon is associated with the fascinating issue to what extent these systems can be classified as molecular wires and thus with the question of the proper mechanism for signal transduction in biomolecules such as proteins. The study of such systems in general is also of interest for the engineering of molecular devices based on the understanding of the transduction of charge by such molecules, thus leading to molecular logic gates-a field of immense current interest.In previous work we have observed some unusual features for electron transfer and hole transfer in polypeptides. In this work the charge was placed on one end of the polypeptide at the C terminus, after which the charge could migrate to the N-terminal portion of the peptide or not. This process was observed to depend in a very sensitive way on the amino acids present in the chain. After experimenting with some 20 synthetic peptides we arrived at a mechanism demonstrating that each amino acid in zero order contributes semi-independently to the electronic surface of the total polypeptide. This surface could be approximated to first order by the values of the ionization potentials (IPs) of the separate amino acids. The IP of the supermolecule was not directly relevant here. Depending on the amino acids, we could then uniquely predict charge mobility or lack thereof. In fact, we could even insert a high-IP amino acid into the chain and stop charge transport at this site. For these reasons we proposed a hoppi...